Issue 32, 2018

Dewetting transitions coupled to K-channel activation in cytochrome c oxidase

Abstract

Cytochrome c oxidase (CcO) drives aerobic respiratory chains in all organisms by transducing the free energy from oxygen reduction into an electrochemical proton gradient across a biological membrane. CcO employs the so-called D- and K-channels for proton uptake, but the molecular mechanism for activation of the K-channel has remained elusive for decades. We show here by combining large-scale atomistic molecular simulations with graph-theoretical water network analysis, and hybrid quantum/classical (QM/MM) free energy calculations, that the K-channel is activated by formation of a reactive oxidized intermediate in the binuclear heme a3/CuB active site. This state induces electrostatic, hydration, and conformational changes that lower the barrier for proton transfer along the K-channel by dewetting pathways that connect the D-channel with the active site. Our combined results reconcile previous experimental findings and indicate that water dynamics plays a decisive role in the proton pumping machinery in CcO.

Graphical abstract: Dewetting transitions coupled to K-channel activation in cytochrome c oxidase

Supplementary files

Article information

Article type
Edge Article
Submitted
07 Apr 2018
Accepted
08 Jul 2018
First published
09 Jul 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2018,9, 6703-6710

Dewetting transitions coupled to K-channel activation in cytochrome c oxidase

S. Supekar and V. R. I. Kaila, Chem. Sci., 2018, 9, 6703 DOI: 10.1039/C8SC01587B

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